Low-Dose Naltrexone for Neuropathic Pain: Mechanistic Plausibility, Phenotype Transferability, and the Limits of Current Clinical Evidence

Low-dose naltrexone (LDN), commonly 1–6 mg/day, is increasingly used off-label for chronic pain, although evidence specific to neuropathic pain remains uncertain. We conducted a structured narrative search of PubMed/MEDLINE, CENTRAL, and ClinicalTrials.gov through 31 July 2026 and classified clinical reports by study design and reported phenotype ascertainment. No placebo-controlled randomized trial was identified in a clinically characterized neuropathic population. One randomized, double-blind, active-control crossover trial in painful diabetic neuropathy, in which both drugs were titrated by early pain response and tolerability, reported an LDN–amitriptyline difference of 1.50 mm on a 0–100 mm visual analog scale (95% confidence interval −1.11 to 4.13), with fewer short-term adverse events under LDN. Interpretation is limited by questions about the reported within-group variance and the crossover analysis, by uncertain adequacy of the treatment and washout durations, and by the absence of placebo or a prespecified equivalence margin. Placebo-controlled evidence from mixed or nociplastic populations shows no consistent clinically meaningful benefit, and its transferability to lesion-based neuropathic pain has not been demonstrated. The TLR4–microglial rationale is plausible, but measured plasma concentrations at 4.5 mg/day fall several orders of magnitude below those associated with TLR4 inhibition in vitro, whereas μ-opioid receptor occupancy is demonstrable within the LDN dose range. Current evidence supports mechanistic plausibility, not established efficacy.